ABSTRACT
Background. ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses with pandemic potential. Our objective was to develop a PPK model that describes the serum ADI concentration time profile following intravenous (IV) and intramuscular (IM) administration. Methods. The ADI PPK model was developed on PK data from a Phase 1 single ascending dose study (24 adults, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE;659 adults, IM) and treatment (STAMP;189 adults, IM) studies. 1,486 PK samples were included in the analysis. The impact of covariates (e.g. body weight, age, and baseline viral load) on ADI serum disposition were evaluated. Prediction-corrected visual predictive check (PC-VPC) plots were used to qualify the PPK model. Participant-specific ADI exposure estimates were generated using individual post hoc PK parameters. Results. The PPK model is comprised of 2 systemic compartments, zero-order infusion for IV administration and first-order absorption for IM administration and provided a robust fit to the data based on the PC-VPC plots and goodness-of-fit plots (data not shown). Body weight influenced clearance, inter compartmental clearance, and central and peripheral volume compartments. The relationship between body weight and clearance was not suggestive of the need for dose adjustment over the population weight range studied (38.6 to 178.7 kg). There was no apparent impact of baseline viral load or age on ADI clearance. The median [range] half-lives in days by study;Phase 1 (alpha1.71 [1.18-2.46];beta 125 [117-149]), Phase 2/3 prevention (alpha 1.86 [0.640-3.13];beta 136 [105-209]), and Phase 2/3 treatment (alpha 1.89 [0.631-3.01];beta 136 [108-206]). The population mean IM bioavailability estimate was 90.5%. The figure shows the PPK model median (90% confidence interval) concentration-time profile following a single 300 mg IM ADI dose by study. Conclusion. The PPK model provided a precise and unbiasedfit to the observed ADI concentration-time data and will be useful for future PK-pharmacodynamic analyses. Moreover, ADI demonstrated high IM bioavailability and a median terminal elimination half-life of 125 to 136 days.